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Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis.

Aoun E, Chang CC, Greer JB, Papachristou GI, Barmada MM, Whitcomb DC - PLoS ONE (2008)

Bottom Line: We found that SPINK1 N34S is strongly associated with CP overall (OR 11.00; 95% CI: 7.59-15.93), but the effect of SPINK1 N34S in alcoholic CP (OR 4.98, 95% CI: 3.16-7.85) was significantly smaller than in idiopathic CP (OR 14.97, 95% C.I. = 9.09-24.67) or tropical CP (OR 19.15, 95% C.I. = 8.83-41.56).The small effect of SPINK1 N34S in alcoholic subjects suggests that CP is driven through a different pathway that is largely trypsin-independent.The results also suggest that large effect sizes of SPINK1 N34S in small candidate gene studies in CP may be related to a mixture of multiple etiologic pathways leading to the same clinical endpoint.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT

Background: The complex interactions between recurrent trypsin-mediated pancreatic injury, alcohol-associated pancreatic injury and SPINK1 polymorphisms in chronic pancreatitis (CP) are undefined. We hypothesize that CP occurs as a result of multiple pathological mechanisms (pathways) that are initiated by different metabolic or environmental factors (etiologies) and may be influenced differentially by downstream genetic risk factors. We tested this hypothesis by evaluating the differences in effect size of the high risk SPINK1 N34S haplotype on CP from multiple etiologies after combining clinical reports of SPINK1 N34S frequency using meta-analysis.

Methods and findings: The Pubmed and the Embase databases were reviewed. We studied 24 reports of SPINK1 N34S in CP (2,421 cases, 4,857 controls) using reported etiological factors as surrogates for pathways and multiple meta-analyses to determine the differential effects of SPINK1 N34S between alcoholic and non-alcoholic etiologies. Using estimates of between-study heterogeneity, we sub-classified our 24 studies into four specific clusters. We found that SPINK1 N34S is strongly associated with CP overall (OR 11.00; 95% CI: 7.59-15.93), but the effect of SPINK1 N34S in alcoholic CP (OR 4.98, 95% CI: 3.16-7.85) was significantly smaller than in idiopathic CP (OR 14.97, 95% C.I. = 9.09-24.67) or tropical CP (OR 19.15, 95% C.I. = 8.83-41.56). Studies analyzing familial CP showed very high heterogeneity suggestive of a complex etiology with an I(2) = 80.95%.

Conclusion: The small effect of SPINK1 N34S in alcoholic subjects suggests that CP is driven through a different pathway that is largely trypsin-independent. The results also suggest that large effect sizes of SPINK1 N34S in small candidate gene studies in CP may be related to a mixture of multiple etiologic pathways leading to the same clinical endpoint.

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Hypothesis of etiology-defined pathways to pancreatic fibrosis.Hypothetical influence diagram illustrating pathologic pathways linking proximal factor (Factor A and B) to PSC (pancreatic stellate cell) and fibrosis through multiple steps (e.g. a1, a2, a3). Etiological factors of type B activate trypsinogen to trypsin, and therefore their pathologic pathway to the PSC can be interrupted by SPINK1. Etiological factors of type A are independent of trypsin, and therefore will not be influenced by variations in SPINK1 expression or function.
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pone-0002003-g001: Hypothesis of etiology-defined pathways to pancreatic fibrosis.Hypothetical influence diagram illustrating pathologic pathways linking proximal factor (Factor A and B) to PSC (pancreatic stellate cell) and fibrosis through multiple steps (e.g. a1, a2, a3). Etiological factors of type B activate trypsinogen to trypsin, and therefore their pathologic pathway to the PSC can be interrupted by SPINK1. Etiological factors of type A are independent of trypsin, and therefore will not be influenced by variations in SPINK1 expression or function.

Mentions: The high-risk SPINK1 N34S haplotype has been observed in one to three percent of most populations, while the incidence of CP is less than one in ten thousand [14], [19]. Furthermore, the reported range of odds ratios (ORs) describing the risk of SPINK1 N34S carriers of developing pancreatitis has varied from non-significance [13] to nearly 80 [15]. Wide variations in reported effects of small genetic association studies have been attributed to statistical variation in underpowered studies, poor methodology, publication bias toward studies with large ORs as well as a myriad of other non-biological factors [20], [21], [22]. However, we hypothesize that in the case of the SPINK1 N34S high-risk haplotype, the variation in reported effect sizes may be a result of differences in the proportion of subjects with pathogenic pathways linking environmental stressors to pancreatic stellate cell (PSC) activation through recurrent trypsinogen activation and inadequate trypsin inhibition by SPINK1. The basic model is illustrated in Figure 1. In this model, SPINK1-regulated pathways would include all upstream etiologic factors associated with recurrent trypsinogen activation (e.g. PRSS1 and CFTR mutations) while SPINK1-independent pathways would include factors that drive PSC to produce fibrosis through mechanisms that are generally independent of recurrent trypsinogen activation (e.g. autoimmune pancreatitis, toxins, pancreatic cancer). Although a number of functionally different risk factors have been statistically associated with alcoholic CP [9], it is not clear if the PSC and fibrosis in alcoholic CP is driven by trypsin-dependent, or independent pathways.


Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis.

Aoun E, Chang CC, Greer JB, Papachristou GI, Barmada MM, Whitcomb DC - PLoS ONE (2008)

Hypothesis of etiology-defined pathways to pancreatic fibrosis.Hypothetical influence diagram illustrating pathologic pathways linking proximal factor (Factor A and B) to PSC (pancreatic stellate cell) and fibrosis through multiple steps (e.g. a1, a2, a3). Etiological factors of type B activate trypsinogen to trypsin, and therefore their pathologic pathway to the PSC can be interrupted by SPINK1. Etiological factors of type A are independent of trypsin, and therefore will not be influenced by variations in SPINK1 expression or function.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2289874&req=5

pone-0002003-g001: Hypothesis of etiology-defined pathways to pancreatic fibrosis.Hypothetical influence diagram illustrating pathologic pathways linking proximal factor (Factor A and B) to PSC (pancreatic stellate cell) and fibrosis through multiple steps (e.g. a1, a2, a3). Etiological factors of type B activate trypsinogen to trypsin, and therefore their pathologic pathway to the PSC can be interrupted by SPINK1. Etiological factors of type A are independent of trypsin, and therefore will not be influenced by variations in SPINK1 expression or function.
Mentions: The high-risk SPINK1 N34S haplotype has been observed in one to three percent of most populations, while the incidence of CP is less than one in ten thousand [14], [19]. Furthermore, the reported range of odds ratios (ORs) describing the risk of SPINK1 N34S carriers of developing pancreatitis has varied from non-significance [13] to nearly 80 [15]. Wide variations in reported effects of small genetic association studies have been attributed to statistical variation in underpowered studies, poor methodology, publication bias toward studies with large ORs as well as a myriad of other non-biological factors [20], [21], [22]. However, we hypothesize that in the case of the SPINK1 N34S high-risk haplotype, the variation in reported effect sizes may be a result of differences in the proportion of subjects with pathogenic pathways linking environmental stressors to pancreatic stellate cell (PSC) activation through recurrent trypsinogen activation and inadequate trypsin inhibition by SPINK1. The basic model is illustrated in Figure 1. In this model, SPINK1-regulated pathways would include all upstream etiologic factors associated with recurrent trypsinogen activation (e.g. PRSS1 and CFTR mutations) while SPINK1-independent pathways would include factors that drive PSC to produce fibrosis through mechanisms that are generally independent of recurrent trypsinogen activation (e.g. autoimmune pancreatitis, toxins, pancreatic cancer). Although a number of functionally different risk factors have been statistically associated with alcoholic CP [9], it is not clear if the PSC and fibrosis in alcoholic CP is driven by trypsin-dependent, or independent pathways.

Bottom Line: We found that SPINK1 N34S is strongly associated with CP overall (OR 11.00; 95% CI: 7.59-15.93), but the effect of SPINK1 N34S in alcoholic CP (OR 4.98, 95% CI: 3.16-7.85) was significantly smaller than in idiopathic CP (OR 14.97, 95% C.I. = 9.09-24.67) or tropical CP (OR 19.15, 95% C.I. = 8.83-41.56).The small effect of SPINK1 N34S in alcoholic subjects suggests that CP is driven through a different pathway that is largely trypsin-independent.The results also suggest that large effect sizes of SPINK1 N34S in small candidate gene studies in CP may be related to a mixture of multiple etiologic pathways leading to the same clinical endpoint.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT

Background: The complex interactions between recurrent trypsin-mediated pancreatic injury, alcohol-associated pancreatic injury and SPINK1 polymorphisms in chronic pancreatitis (CP) are undefined. We hypothesize that CP occurs as a result of multiple pathological mechanisms (pathways) that are initiated by different metabolic or environmental factors (etiologies) and may be influenced differentially by downstream genetic risk factors. We tested this hypothesis by evaluating the differences in effect size of the high risk SPINK1 N34S haplotype on CP from multiple etiologies after combining clinical reports of SPINK1 N34S frequency using meta-analysis.

Methods and findings: The Pubmed and the Embase databases were reviewed. We studied 24 reports of SPINK1 N34S in CP (2,421 cases, 4,857 controls) using reported etiological factors as surrogates for pathways and multiple meta-analyses to determine the differential effects of SPINK1 N34S between alcoholic and non-alcoholic etiologies. Using estimates of between-study heterogeneity, we sub-classified our 24 studies into four specific clusters. We found that SPINK1 N34S is strongly associated with CP overall (OR 11.00; 95% CI: 7.59-15.93), but the effect of SPINK1 N34S in alcoholic CP (OR 4.98, 95% CI: 3.16-7.85) was significantly smaller than in idiopathic CP (OR 14.97, 95% C.I. = 9.09-24.67) or tropical CP (OR 19.15, 95% C.I. = 8.83-41.56). Studies analyzing familial CP showed very high heterogeneity suggestive of a complex etiology with an I(2) = 80.95%.

Conclusion: The small effect of SPINK1 N34S in alcoholic subjects suggests that CP is driven through a different pathway that is largely trypsin-independent. The results also suggest that large effect sizes of SPINK1 N34S in small candidate gene studies in CP may be related to a mixture of multiple etiologic pathways leading to the same clinical endpoint.

Show MeSH
Related in: MedlinePlus